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ABSTRACT

Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis work in concert to control many stages of this process, and when one is impaired it leads to failure of bone healing, termed a nonunion. During fracture repair, there is an infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but we hypothesize they also exert influence on neovasculature. Thus, further understanding the effects of immune cell participation throughout fracture healing will reveal additional knowledge as to why some fractures heal while others form nonunions, and lead to development of novel therapeutics modulating immune cells, to increase fracture healing and prevent nonunions. Using novel femoral segmental and critical-size defect models in mice, we identified a systemic and significant increase in immature myeloid cell (IMC) infiltration during the initial phase of fracture healing until boney union is complete. Using gemcitabine to specifically ablate the IMC population, we confirmed delayed bone healing. Further, adoptive transfer of IMC increased bone growth in a nonunion model, signifying the role of this unique cell population in fracture healing. We also identified IMC post-fracture have the ability to increase endothelial cell migration, and tube formation, signaling the essential communication between the immune system and angiogenesis as a requirement for proper bone healing. Based on this data we propose that IMC may play a significant role in fracture healing and therapeutic targeting of IMC after fracture would minimize the chances of eventual nonunion pathology.

4. Discussion

Immature myeloid cells are a population of immune cells which under normal conditions mature into macrophages, dendritic cells,and granulocytes. IMC are also capable of suppressing the immune response of T lymphocytes and are known to induce angiogenesis within tumors [14]. Furthermore, Yang et al. reported that colorectal tumor cells co-injected with myeloid cells exhibited not only increased vessel density and maturation, but that myeloid cells can directly incorporate into the tumor endothelia [38]. The IMC compartment represents approximately 30% of the bone marrow in normal mice, yet their role as inflammatory mediators in bone fracture has not been elucidated. The present study identified a critical and novel role of IMC in fracture healing and how IMC influence the overlapping phases of inflammation, angiogenesis, and osteogenesis after bone fracture. Compared to normal fractures, mice treated with gemcitabine to selectively deplete IMC population demonstrated an inability to heal fractures, while adoptive transfer of IMC obtained only from mice bearing fractures in a critical size defect increased bone growth following fracture. Evaluation of IMC after fracture revealed a significant upregulation in the expression of angiogenic genes, and the ability to bind to and increase the motility and mobility of endothelial cells in vitro. Results of these studies clearly demonstrate IMC likely contributed to the growth and formation of blood vessels after bone fracture and their presence was vital for proper fracture healing.